The role and mechanism of METTL14 in regulating pyroptosis via m6A methylation across multiple diseases: A Systematic review.

N6-methyladenosine (m⁶A), the most abundant internal RNA modification in eukaryotes, plays a critical role in post-transcriptional regulation. METTL14, a core component of the methyltransferase complex, emerges as a key epigenetic regulator with diverse functions in physiology and disease. Accumulating evidence reveals that METTL14 governs pyroptosis, a pro-inflammatory form of programmed cell death, via m⁶A-dependent mechanisms across various diseases, including neurological, cardiovascular, skeletal, and metabolic disorders. Importantly, m⁶A modification is implicated in multiple forms of regulated cell death beyond pyroptosis, such as apoptosis, ferroptosis, and necroptosis, highlighting the broad regulatory potential of METTL14 in cell fate decisions.This review systematically synthesizes the current knowledge on how METTL14 modulates pyroptosis by targeting key components (e.g., NLR Family Pyrin Domain Containing 3 (NLRP3), gasdermin D (GSDMD)) or regulatory non-coding RNAs, thereby influencing disease progression. We highlight the context-dependent duality of METTL14, which can either promote or suppress pyroptosis depending on the specific pathological milieu. Furthermore, we discuss the associated challenges and future therapeutic prospects, emphasizing the need for context-specific strategies, advanced drug delivery systems, and integrated multi-omics approaches to harness the potential of targeting METTL14 in treating inflammatory and degenerative diseases.